Now, a new study led by Chu Chen, PhD, professor in the Department of Cellular and Integrative Physiology and Joe R. and Teresa Lozano Long Chair in neural physiology in the Long School of Medicine at The University of Texas at San Antonio, suggests a combination approach may provide the benefits of THC treatment with fewer negative side effects.

In Chen’s study, published in December 2025 in Aging and Disease, his team paired a low-dose THC extract with the selective anti-inflammatory drug celecoxib. When used in mice, the combo improved cognition and reduced Alzheimer’s-related brain pathology.

Both drugs are already Food and Drug Administration-approved for use in humans, pointing to a potential fast track to clinical trials.

Inflammation at root of many diseases

Chen began his query more than a decade ago into how THC impairs learning and memory. In a 2013 study, his lab uncovered a key molecular driver. Cyclooxygenase-2 (COX-2) is an enzyme known for its role in inflammation and pain. It is normally expressed at low levels in the brain but becomes activated during injury, infection or disease. COX-2 also plays a role in synaptic plasticity, including long-term potentiation, a cellular process essential for learning and memory.

“When THC is given, it unexpectedly increases COX-2 in the brain. That increase is closely associated with learning and memory impairment,” Chen said.

The discovery helped explain why THC has been difficult to use safely for neurological conditions. Globally blocking COX-2 is not a solution either. Previous clinical trials using high doses of COX-2 inhibitors for Alzheimer’s disease did not show cognitive benefits and additionally produced detrimental cardiovascular side effects.

Same receptor, opposite outcomes

Endocannabinoids cannabinoids produced within the brain act on the same cannabinoid receptors as external THC but often exert opposite or regulatory effects. Among them, 2-arachidonoylglycerol (2-AG) is a key endocannabinoid that engages signaling pathways that lead to reduced COX-2 activity and less neuroinflammation.

This insight prompted Chen to consider if the pro-inflammatory effects of THC could be blocked while preserving its beneficial actions.

Combination drug in Alzheimer’s models

Chen’s team chose to add celecoxib, a selective COX-2 inhibitor widely prescribed for arthritis and pain. The researchers used very low doses, far below those associated with cardiovascular risk in earlier Alzheimer’s trials. For the study, they administered 3 mg/kg of THC and 1 mg/kg of celecoxib per day to mice. This is the human-equivalent in a 165-pound person of 18 mg THC and 6 mg of celecoxib per day.

In the new study, the researchers tested low-dose THC alone and in combination with celecoxib in beta-amyloid and tau mouse models of Alzheimer’s disease. Beta-amyloid plaques and tau tangles are central hallmarks of Alzheimer’s.

Treatment was initiated prior to the development of memory symptoms to concentrate on the combination’s effect in preventing or delaying the onset of Alzheimer’s symptoms. Oral doses were given once daily for 30 days.

The results were consistent across both the beta-amyloid and tau models. Although low-dose THC alone improved cognitive performance and reduced some pathological markers, it also increased inflammatory signaling. In contrast, the combination of THC and celecoxib produced better outcomes, including improved learning and memory performance, reduced beta-amyloid and tau pathology, and decreased markers of neuroinflammation.

Single-cell RNA sequencing revealed that genes involved in synaptic function, inflammation and Alzheimer’s disease risk were shifted back toward a healthier profile following the treatment.

“What really mattered was behavior. If cognition is not improved, then the treatment doesn’t matter. And that’s where the combination clearly worked better than THC alone,” Chen said.

Source: https://news.uthscsa.edu/ut-health-san-antonio-research-shows-alzheimers-prevention-potential-in-pairing-cannabis-ingredient-anti-inflammatory-drug/